title: STRAP regulates c-Jun ubiquitin-mediated proteolysis and cellular proliferation.
abstract: STRAP is a ubiquitous WD40 protein that has been implicated in tumorigenesis. Previous studies suggest that STRAP imparts oncogenic characteristics to cells by promoting ERK and pRb phosphorylation. While these findings suggest that STRAP can activate mitogenic signaling pathways, the effects of STRAP on other MAPK pathways have not been investigated. Herein, we report that STRAP regulates the expression of the c-Jun proto-oncogene in mouse embryonic fibroblasts. Loss of STRAP expression results in reduced phospho-c-Jun and total c-Jun but does not significantly reduce the level of two other early response genes, c-Myc and c-Fos. STRAP knockout also decreases expression of the AP-1 target gene, cyclin D1, which is accompanied by a reduction in cell growth. No significant differences in JNK activity or basal c-Jun mRNA levels were observed between wild type and STRAP null fibroblasts. However, proteasomal inhibition markedly increases c-Jun expression in STRAP knockout MEFs and STRAP over-expression decreases the ubiquitylation of c-Jun in 293T cells. Loss of STRAP accelerates c-Jun turnover in fibroblasts and ectopic over-expression of STRAP in STRAP null fibroblasts increases c-Jun expression. Collectively, our findings indicate that STRAP regulates c-Jun stability by decreasing the ubiquitylation and proteosomal degradation of c-Jun.
authors.affiliation: Department of Cancer Biology, Vanderbilt University, School of Medicine, Nashville, TN, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Reiner
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.forename: Nilesh D
authors.initials: ND
authors.lastname: Kashikar
authors.forename: Pran K
authors.initials: PK
authors.lastname: Datta
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D049109:Cell Proliferation; D004795:Enzyme Stability; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D016601:RNA-Binding Proteins; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000715470:MAS1 protein, human; D011506:Proteins; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun; D016601:RNA-Binding Proteins; C116758:STRAP protein, mouse; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex